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Project 1 - Toxicity and Liver Carcinogenicity of 1,4-Dioxane: Single Chemical and Mixtures Studies

项目 1 - 1,4-二恶烷的毒性和肝脏致癌性：单一化学品和混合物研究

基本信息

批准号：
10698005
负责人：
Ying Chen
金额：
$ 22.57万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-07 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10698005
关键词：
Animals Biological Biological Markers Biological Models CYP2E1 gene Carcinogens Cells Chemicals Chronic Classification Communication DNA Damage Data Analyses Development Dioxanes Dose Ethylene Dichlorides Event Exposure to Fostering GCLC gene GCLM gene Gamma-H2AX Genetic Glutathione Goals Health Hepatocarcinogenesis Hepatocyte Hepatotoxicity Homeostasis Human In Vitro International Agency for Research on Cancer Lipid Peroxidation Liver Long Island Malignant Neoplasms Malignant neoplasm of liver Molecular Molecular Target Mouse Strains Mus NQO1 gene Oncogenes Organ Oxidation-Reduction Pathway interactions Pattern Persons Phase Phenotype Plasma Predisposition Process Proteins Rattus Reactive Oxygen Species Research Resources Risk Role Safety Site Source Subgroup Superfund Time Toxic effect Transgenic Organisms Translational Research Trichloroethylene Uncertainty Urine Water Pollutants Xenobiotics Zebrafish adverse outcome carcinogenicity cytotoxicity drinking water exposed human population genotoxicity high throughput screening in vitro Assay in vivo liver cancer model metabolomics mouse model multiple omics novel oxidation programs promoter response screening sound stem transcriptome sequencing translational potential tumor

项目摘要

PROJECT SUMMARY 1,4-Dioxane (1,4-DX) is an emerging drinking water contaminant. The potential for 1,4-DX exposure is elevated for people living near Superfund or other types of 1,4-DX release sites. The International Agency for Research on Cancer has classified 1,4-DX as a group 2B carcinogen with the primary organ target being the liver in animal studies. Despite this concern, safety standards for 1,4-DX in drinking water have been slow to develop and vary widely, with the variability being related to the uncertainty associated with its liver carcinogenic potential. Mechanistic studies are urgently needed to (i) understand how 1,4-DX may contribute to liver carcinogenesis by itself or in combination with other co-occurring drinking water contaminants [such as trichloroethylene (TCE) and 1,1-dichloroethane (1,1-DCA)], (ii) determine the exposure concentration range over which these effects occur, and (iii) identify potentially more vulnerable subgroups. Our preliminary studies in mice have revealed molecular targets and pathways potentially involved in 1,4-DX carcinogenicity and set the stage for the proposed studies. These preliminary studies utilized various 1,4-DX concentrations (50, 500 and 5,000 ppm) in drinking water for periods of up to 3 month. These studies revealed mild liver cytotoxicity that is consistent with previous studies. The highest 1,4-DX dose induced assorted molecular changes in the liver including: (i) persistent induction of NRF2 and its target proteins involved in anti-oxidative response (i.e., GCLC, GCLM, HMOX1 and NQO1), (ii) time-dependent induction of CYP2E1 (key oxidative pathway capable of activating endogenous and xenobiotic compounds and a generator of reactive oxygen species), (iii) centrilobular accumulation of the lipid peroxidation by-product 4-HNE, and (iv) elevations in the DNA damage marker γH2AX. Importantly, these 1,4-DX-elicited molecular changes were amplified in a mouse model of systemic glutathione (GSH) deficiency. This project will build upon these intriguing findings and investigate our novel hypothesis predicting that long-term exposure to 1,4-DX causes liver tumorigenesis by disrupting redox homeostasis, thereby potentiating genetic instability. This proposed 1,4-DX mode of action would be of high relevance in assessing carcinogenic effects of co-occurring contaminants that may utilize or modulate overlapping molecular pathways. We propose to (1) delineate the contribution of key redox pathways to 1,4-DX liver carcinogenicity in vivo using transgenic redox mouse models, (2) identify the biological network motifs that predict 1,4-DX-induced liver carcinogenesis and the dose response pattern for perturbation of these networks in vivo, and (3) elucidate the capacity of co-occurring contaminants (TCE and 1,1-DCA) to modify 1,4-DX carcinogenicity in human hepatocyte cells and zebrafish model systems.

项目总结